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Briefing Paper on
Biological and Biosimilar Medicines
Contents
Foreword: Kin-ping Tsang, Chair, International Alliance of Patients’ Organizations
3
Executive summary
4
Part one: Biological and biosimilar medicines
5
What is biotechnology?
5
What is a biological medicine?
5
How are they produced?
5
How are biological medicines different from traditional chemical medicines?
6
How do these differences impact the patient?
7
What is a biosimilar medicine?
Why are biosimilar medicines being made?
9
How to ensure quality, safety and efficacy
9
How are biosimilar medicines developed?
10
How are biosimilars regulated and by whom?
10
Influential regulatory pathways and guidelines for biosimilar medicines
11
What categories of biosimilars are currently available?
12
What has been the impact of biosimilar medicines?
12
What next for biosimilars?
13
Part two: What matters to patients
With our thanks
IAPO would like to thank all those involved in planning this Toolkit and supporting its development. A full list of acknowledgements
can be found at the end of this Briefing Paper.
IAPO’s project on biosimilar medicines has been made possible thanks to educational grants from Amgen and Lilly USA, LLC (for
the Toolkit) and Merck Serono and the Pharmaceutical Research and Manufacturers of America (PhRMA) (for IAPO’s Workshop on
Biosimilar Medicines, 2013).
© November 2013 IAPO. All rights reserved.
IAPO is registered as an Association in The Netherlands.
Registration Number: 30201854
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participants in this Toolkit are their own and not necessarily those of IAPO. Reference to any person or organization in this Toolkit
does not imply that such a person has been approved or recommended by IAPO.
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8
What do patients need to know about the safety of biosimilar medicines?
15
16
Could there be adverse effects?
16
What systems are in place to monitor medicine safety?
17
What’s in a name – what should patients report in case of an adverse effect?
18
What are patients being prescribed?
19
When is a biosimilar not a biosimilar?
20
Who can access biological and biosimilar medicines?
22
What information and support is available for patients?
23
Should patients be involved?
25
Conclusions and recommendations
27
Review process and acknowledgements
29
Glossary
31
References
34
Appendix
36
Foreword
The International Alliance of Patients’ Organizations (IAPO) has a core value of involving patients and patients’
organizations in debate and policy-making at the international, regional, national and local levels. In order for patients’
organizations to be meaningfully involved in the debate and effective advocates, they must be well informed on the
issues that are, or will be, affecting patients’ lives.
In 2006 IAPO published a briefing paper to educate and inform patients’ organizations on the introduction of biological
and biosimilar medicines. The briefing paper outlined issues for consideration by patients and patients’ organizations
and brought together stakeholder perspectives on the most important issues relating to the introduction of biosimilar
medicines. It was provided free of charge to over 1,000 patients’ organizations around the world and at the time was
the only document of its kind developed specifically for patients and patients’ organizations.
Since 2006, there have been many developments in biological and biosimilar medicines, with biosimilar medicines
coming to market in a number of countries. This raises the need for patients’ organizations and patients to be informed
as to the situation and what it means for them. Over the coming years, more biological and biosimilar medicines will
become available to patients worldwide, providing an exciting opportunity to take stock and provide new and updated
information regarding these medicines to patients. There will also be the need to explore issues such as regulation and
transparency, access, patient information and support, and patient involvement in decision-making.
This Briefing Paper aims to provide patients’ organizations with up-to-date, evidence-based information on the science,
technology and regulatory information relevant to biological and biosimilar medicines. IAPO hopes these resources will
allow patient advocates to make informed judgements on the value of biological and biosimilar medicines and actively
engage in debate and discussion with other stakeholders involved in healthcare.
In May 2013, IAPO held a Workshop on Biosimilar Medicines which brought together 19 patients’ organization
representatives and other healthcare stakeholders from around the world to participate in an exciting programme
which explored the impact of biological and biosimilar medicines on patient care, including issues of access and
availability. Issues arising from discussions during the workshop have also informed the content of this Briefing Paper.
This Briefing Paper is part of a wider Information and Advocacy Toolkit on Biological and Biosimilar Medicines, which
contains a quick guide on biosimilar medicines, a guide on what patients’ organizations can do, fact sheets, and a
number of additional resources. We hope these resources will continue to inform patients’ organizations globally.
Kin-ping Tsang
Chair, International Alliance of Patients’ Organizations
3
Executive summary
Part one: Biological and biosimilar medicines
Biological medicines are made from living organisms using biotechnology techniques. Since their introduction in
the 1980s they have revolutionized the treatment of many diseases such as cancers, diabetes, autoimmune diseases
such as rheumatoid arthritis, heart attacks, stroke, and multiple sclerosis, and for a number of rare disorders. They
have benefited millions of patients worldwide. As many of these original biological medicines reached the end of their
patents, other manufacturers were able to produce highly similar versions of these medicines. These highly similar
versions of biological medicines are commonly called biosimilar medicines.
What is biotechnology?
Biotechnology is increasingly associated with the production of medicines. It is the application of scientific and
engineering methods to manipulate living organisms such as bacteria or yeast in order to produce goods and services.1
Over the years, certain milestones in science, such as the work of Louis Pasteur in understanding microbiology, the
discovery of antibiotics, such as penicillin, and the discovery of the structure of DNA,1 have allowed for biotechnology
to be used in the development of new medicines. In the 1970s, scientists used genetic engineering techniques,
which manipulated the genes of living organisms such as plant or animal cells, bacteria, yeast and viruses, to make
therapeutic proteins,2 revolutionising the diagnosis, prevention, cure and management of a wide range of serious and
chronic diseases.
At a time when the burden of chronic diseases is increasing across the world, ensuring that patients can access safe,
quality, affordable and modern medicines such as biological medicines is vital to improving health. There are many
barriers to patient access to new medicines, one of which is cost. In the coming decade we expect a great number of
biosimilar medicines to become available for patients worldwide. These will provide alternative medicines for patients,
usually at a lower cost than the original biological medicine, making these lifesaving medicines more accessible, and
will increase options for doctors, patients and healthcare systems in general.
“
At a time when the burden of chronic diseases is increasing across the world, ensuring
that patients can access safe, quality, affordable and modern medicines such as biological
medicines is vital to improving health.
”
What is a biological medicine?
Biological medicines contain active substances (substances that produce the desired therapeutic effect) that are
produced by, or extracted from, living organisms. They are often made up of proteins that are naturally produced in the
human body. When a biological medicine is given to a patient, it functions like the natural protein, resolving symptoms
and preventing or slowing the progression of the disease.
Since the 1980s, when the first biotechnology medicines were made available to patients, these medicines have helped
to treat diseases such as cancers, diabetes, multiple sclerosis, heart attacks, stroke and autoimmune diseases such as
rheumatoid arthritis.
There are a wide range of biological medicines including:3–5
As with all medicines, patients need to be able to make a fully informed decision about whether to take a biological or
biosimilar medicine or not, and to be fully involved in deciding what treatment to pursue together with their healthcare
team. It is therefore essential that patients have access to clear and impartial information about what biological and
biosimilar medicines are, and what their growing availability will mean for them.
This IAPO Briefing Paper on Biological and Biosimilar Medicines, as part of a wider Toolkit, aims to provide detailed
information about biosimilar medicines for patients’ organizations, and explore patients’ views revealed during research.
¢
¢
4
Part one of this Briefing Paper provides a comprehensive overview of what biological and biosimilar medicines are,
how they differ from other medicines, how they are developed and regulated, and their current impact and
potential impact in the coming years.
Part two explores what really matters to patients and patients’ organizations, highlighting the questions that
patients asked during an online consultation and during interviews. It also explores the views of a variety of different
healthcare stakeholders.
¢
hormones for hormone deficiencies e.g. insulin for diabetes and growth hormone for growth hormone disorders
¢
monoclonal antibodies for the treatment of autoimmune diseases and cancers
¢
blood products e.g. for the treatment of haemophilia
¢
immunomodulators e.g. beta-interferon for multiple sclerosis
¢
enzymes e.g. to remove blood clots
¢
vaccines to prevent a number of diseases.
How are they produced?
The majority of biological medicines are produced using genetically modified cells. These are cells whose genes have
been changed, using recombinant DNA techniques, so that they produce a substance or perform a function, i.e. the
genes for a certain protein would be introduced into the genes of a host cell (such as a bacteria or yeast cell), which
would consequently produce that protein. Each biological medicine manufacturer has its own host cell bank, producing
a unique cell line, and develops its own unique manufacturing process.6
5
Table 1. Major differences between traditional chemical medicines and biological medicines [NB: images not to scale]
Here is how it happens:3,7
1. First the genetic code (a sequence of DNA) of a chosen protein (e.g. a hormone, antibody, blood product) is
identified and a functional DNA sequence created.
Traditional chemical medicines
Biological medicines
Small, simple structure which is easy to characterize.
Medium to very large, complex structure which is difficult to
characterize.
2. The genetic code is inserted into various host cell lines (e.g. bacteria or yeast), so that the host cells produce this protein.
3. The host cell line that produces the protein most effectively is chosen.
4. This cell line is then grown in machines called bioreactors; this process is called fermentation.
5. The protein is separated out of the bioreactor (e.g. though filtration).
6. The protein is purified, stabilised and processed into a medicine (e.g. insulin injections).
Source
DNA
E.g. average size of human growth hormone: 3,091 atoms
Target
DNA
Gene sequence of
desired protein identified
Functional DNA
sequence created
DNA sequence inserted into
a host cell, e.g. bacteria
Image provided by Amgen
Purified bulk drug
Protein purified, stabilised
and processed into a medicine
Protein separated from cells
via filtration / centrifugation
Cell line producing protein
most effectively is chosen and
grown in a bioreactor
Figure 1. Steps in the production of a biological medicine
This process is complex and sensitive to change. The physical and chemical properties of the final medicine can be
influenced by a number of variables, including changes in the manufacturing process (e.g. the material that the
bioreactor is made from), and the handling, packaging, transport and storage processes. These changes could make
the medicine less effective. It can be difficult to ensure consistency from one production cycle to the next. For these
reasons, the production of biological medicines requires a high level of technical expertise and the process must be very
carefully controlled and monitored to ensure the safety, efficacy and quality of the final medicine.
How are biological medicines different from traditional chemical medicines?
A biological medicine is very different from a traditional, synthetic chemical drug such as paracetamol or aspirin. As a
patient it is important to understand the implications of these differences.
Traditional chemical medicines are made by using chemical reactions which can be easily reproduced and wellcontrolled.8 They are often small and stable molecules. Their structure can be completely and easily worked out using a
number of analytical methods.5
As explained above, the production process of biological medicines is much more complicated. They are larger, more
complex molecules (see Table 1).9 As they are made in living organisms such as animal cells, yeast or bacteria, there will
always be some differences in the make-up of biological medicines.8,10 Compared to a chemical medicine, it is much
more difficult to work out the full structure and make-up of a biological medicine.
6
E.g. average size of aspirin: 21 atoms
E.g. average size of an antibody: >20,000 atoms
Homogenous – all structures identical, well-defined and have
predictable chemical structure/properties; easy to reproduce
exactly
Heterogeneous – mixed structure, less predictable biological
properties and structure; difficult to reproduce exactly
Produced by a step-by-step simple chemical synthesis process.
Drug can be produced within days
Produced by a biological synthesis process using modified living
cells via complex fermentation and purification processes.
Long production cycles (weeks/months)
Quality checks needed but only on the performance of end
product
Quality checks are needed throughout the manufacturing process
and on the performance of end product
Often stable for long periods of time
Less stable – changes in manufacturing processes such as high
temperature or incorrect storage can lead to degradation of the
medicine and affect safety and/or efficacy
How do these differences impact the patient?
Biological medicines are often administered by injection or infusion in a hospital setting and have to be stored
very carefully to avoid spoiling.5,11 Furthermore, all medicines can induce an immune response in the body such as
hypersensitivity or an allergy. While chemical medicines can cause immune responses, they tend to be rare. Biological
medicines on the other hand can more frequently cause an immune response from the body due to their large and
complex structure.5 The ability to cause an immune response is called immunogenicity.
Changes in production methods or impurities can cause changes in the biological medicines which may affect their
likelihood of causing an immune reaction.12,13 In most cases this will not be significant, but in some cases it can be lifethreatening. Immunogenicity will be discussed in more detail on page 16.
7
Table 2. Differences in how traditional chemical medicines and biological medicines impact patients
Traditional chemical medicines
Biological medicines
Unlikely to cause an immune reaction in the body due to small
molecular size
More likely to cause an immune reaction in the body due to
large molecular size and composition
Often taken orally in tablet or capsule form
Often administered by injection or infusion, as proteins are
affected by the digestive system when taken orally
Usually prescribed by general practitioner or primary care
physician
Usually used for the treatment of more severe diseases and often
prescribed by specialists
Can often be self-administered at home
Often administered in hospital with the help of medical staff or
self-administered through sub-cutaneous injections
Why are biosimilar medicines being made?
Biological medicines have revolutionised the treatment of a number of diseases that were previously untreatable.
However, access for patients globally can be limited or difficult due to high costs, including development, materials and
manufacturing costs which are much higher than traditional chemical medicines.3
The availability of biosimilar medicines could promote competition and bring down the price of biological medicines
for the payer, and deliver cost savings.3 This means that patients may be able to access medicines which are lifesaving
but may have previously been unaffordable both to health systems and patients. For example, when combinations of
drugs are needed for the treatment of a certain disease, if one of these drugs were available as a biosimilar, the cost of
treatment would decrease. Availability of lower cost biosimilar medicines could also free up funds in healthcare systems
which could then be reallocated to other areas in need. Furthermore, the availability of biosimilar medicines on the
market could enhance competition18 and stimulate the development of new, innovative biological medicines.
Key definitions
What is a biosimilar medicine?
When a drug is developed, the company that has the patent has control over who can manufacture and sell the
medicine. However, once this patent period runs out, other companies are allowed to manufacture and sell the
drug as well. This can decrease the cost of the drug on the market. As chemical medicines have simple structures
that are easy to work out, it is relatively easy to produce what can be considered an identical version of the original
drug with the same active ingredient, safety and efficacy profile.14 Copies of traditional chemical drugs are called
‘generic medicines’. For example, when a patient goes into a pharmacy to buy some ibuprofen (a painkiller) or
collect a prescription for simvastatin (for high cholesterol), they can either buy the branded version or they can buy an
unbranded, i.e. generic, version. The generic version is identical to the branded version but will often be significantly
cheaper. Like generic medicines, biosimilar medicines may be produced upon expiration of the original patent.
However, they are not generic medicines.
Biotechnology: The United Nations Convention on Biological Diversity defines biotechnology as “any technological
application that uses biological systems, living organisms or derivatives thereof, to make or modify products or processes for
specific use”.
A biosimilar medicine is developed to be highly similar to a biological medicine that is already approved and
available for patients, once the original patent has expired. The medicine that has already been approved is often called
the ‘reference product’ or ‘originator product’.15 A variety of terminology to describe biosimilar medicines is used across
the world (see Glossary). In this Briefing Paper we will use the term ‘biosimilar medicine’, which is often shortened
to ‘biosimilars’, and the term ‘reference product’ to describe the medicine that the biosimilar medicine has been
developed to be similar to.
European Medicines Agency definition: A biological medicine that is developed to be similar to an existing biological medicine.
When approved, its variability and any differences between it and its reference medicine will have been shown not to affect
safety or effectiveness.
Unlike chemical medicines, it is not possible to produce an exact copy of a biological medicine. This is due to the large,
complex structure of biological medicines, the fact that they are produced in living organisms and that they are very
dependent on the manufacturing process. Due to these factors, no two biological medicines can be considered exactly
the same, and a degree of variability is natural in all biological medicines. This variability can exist within different
batches of any given biological medicine and when production processes are improved or changed, or differ between
manufacturers.16
How to ensure quality, safety and efficacy
How do we know that a biosimilar medicine is highly similar to the reference product in terms of quality, safety and
efficacy? The basic principle underlying the development and approval of a biosimilar medicine is that it is comparable to
the reference product. This is assessed through a ‘biosimilar comparability exercise’, where the biological product is
compared to the reference product in terms of quality, safety and efficacy (full details of this can be found on pages 9–10).13
A comparability exercise is not undertaken to establish the therapeutic benefit of the biosimilar medicine, but to show that
it is highly similar to the reference product and that there are no significant differences to its quality, safety and efficacy.14
Once a biosimilar medicine has gone through a stringent regulatory process and is approved (see page 10), although
it is not identical to its reference product, it is highly similar to the reference product in terms of quality, safety
and efficacy. In other words, any differences between the reference product and biosimilar medicines have been
shown not to affect quality, safety and efficacy. As it is impossible to produce exact copies of biological medicines,
regulators of medicines acknowledged that biosimilar medicines required a novel and rigorous testing, approval and
regulatory system that is different to the approval of generic medicines, and to that of a new biological medicine. The
first regulatory process for biosimilar medicines was developed in Europe in 2005 by the European Medicines Agency
(EMA).17 Further information about regulation of biosimilars can be found on page 10.
It is important to remember that a biosimilar medicine is a biological medicine itself. They are made using exactly the
same biotechnology techniques and processes as described on pages 5–6.
Biological medicine (also called biopharmaceutical medicine, biotechnology medicine or biotherapeutic medicinal
product): The active substance of a biological medicinal product is a biological substance. A biological substance is a
substance that is produced by, or extracted from, a biological source. A combination of physico-chemical-biological testing, its
production process and control is needed to characterise it and determine its quality.
Biosimilar medicine: A biosimilar medicine is a highly similar version of an already-approved biological medicine, in terms of
quality, safety and efficacy.
World Health Organization definition (also called a similar biotherapeutic product): A biotherapeutic product which is similar in
terms of quality, safety and efficacy to an already-licensed reference biotherapeutic product.
US Food and Drug Administration definition: A biological product that is highly similar to a US-licensed reference biological
product, notwithstanding minor differences between the biological product and the reference product in terms of safety, purity
and potency of the product.
Biosimilars at a glance
A biosimilar medicine is a highly similar version of a reference biological medicine (i.e. one that has already
been approved).
¢
It has comparable quality, safety and efficacy as the reference product.
¢
This is shown through a biosimilar comparability exercise.
¢
They are developed in order to provide alternative products usually at lower cost and increase options for
clinicians, payers and healthcare systems in general.
¢
¢
8
Like all biological medicines, they have to be carefully regulated as they are complex, large, structurally
unstable molecules which are produced in living organisms.
9
How are biosimilar medicines developed?
Biosimilar medicines are developed in a systematic, step-by-step approach. The aim of this approach is to ensure that
the biosimilar product is highly similar to the reference product in terms of quality, safety and efficacy.14,19
First the reference product is defined using sophisticated analytical tools and existing clinical knowledge. A development
and manufacturing process for the biosimilar medicine is put in place to match the variability of the reference product.
Once the medicine is produced it is compared to the reference product in a biosimilar comparability exercise.
There are three steps in the comparability exercise. The first is to show the quality is comparable. In this step the
physicochemical and biological qualities are compared through a series of analytical tests.
The second stage is non-clinical comparability. This includes dosing studies, and examining what the body does to
the drug and what the drug does to the body in appropriate animal models to detect any differences between the
biosimilar medicine and the reference product.
The third stage is clinical comparability, where the biosimilar medicine is tested in humans in a clinical trial. A
comparable safety profile in terms of seriousness and frequency of side effects must also be shown at this point.
Characterise
reference
product
Develop
manufacturing
process for
biosimilar
Influential regulatory pathways and guidelines for biosimilar medicines
Europe: The European Union was the first region to set up a legal framework and regulatory pathway for the approval
of biosimilar medicines.6 In Europe, the European Medicines Agency is responsible for assessing all applications for both
biological medicines and biosimilar medicines, and for several post-authorization activities. The EMA published its initial
regulatory guidelines in 2005.17 These outlined how to compare the reference product and the biosimilar. The EMA has
developed overarching, product-specific, quality, clinical and non-clinical issue guidelines for biosimilars.17 These are
revised on a regular basis by the Biosimilar Medicinal Products Working Party (BMWP) of the EMA to ensure they are up
to date and take into account experience with biosimilars and advances in science and technology.
World Health Organization: In April 2010, the World Health Organization (WHO) published their Guidelines on
Evaluation of Similar Biotherapeutic Products.14 These guidelines aimed to provide a set of globally acceptable principles
to approve biosimilar medicines that would assure quality, safety and efficacy. WHO suggested the Guidelines could be
adopted as a whole, partially, or could be the basis for developing a regulatory pathway.
North America: The United States has had a legal pathway for the approval of biosimilar medicines in place since
March 2010.22 However, it was only in February 2012 that the Food and Drug Administration (FDA) released three
draft guidance documents for the development of biosimilar medicines. This guidance is intended to help define the
pathway for approval of biosimilar medicines under an abbreviated Biologic License Application that allows a biosimilar
product to be evaluated against a single reference product.22
Conduct comparability exercise:
Develop
biosimilar
medicine
1. Quality comparability
2. Non-clinical comparability
3. Clinical comparability
In Canada, Health Canada finalised guidelines for biosimilar medicine in March 2010.23 Canadian guidelines include
specific guidelines for different types of biosimilar medicines, and a question and answer document.24
EMA
Guideline
WHO
Guideline
FDA Draft
Guideline
Figure 2. Stages of development of a biosimilar medicine
2005
The non-clinical and clinical comparability provides the confidence that any differences observed at the quality
comparability level do not have any impact on the safety and efficacy of the biosimilar medicine. The clinical data is
not intended to show the benefit of the medicine, but to ensure that any differences have no impact on its quality and
safety.20 The amount of non-clinical and clinical data needed depends on how complete the quality data is, and on the
product or type of product.14 Often clinical studies for biosimilar medicines will be smaller and shorter than those for
the reference product.
Once all the data from the comparability exercise has been collected, it is then submitted to the appropriate regulatory
body, along with a plan to manage risk. The plan to manage risk describes the safety profile of the medicine and
outlines how the manufacturer will further monitor and fill any gaps in the data regarding safety and efficacy.19 The
regulatory body will assess the comparability data, risk management plan and plans for monitoring after the medicine is
made available to determine whether the biosimilar should be approved.i
How are biosimilars regulated and by whom?
Biosimilar medicines need a different regulatory pathway from that of a new biological drug or from a generic chemical
drug. This pathway is often called an abbreviated licensing pathway as it is a shorter version of the pathway used to
approve a new biological medicine.21 The European Union paved the way for the regulation and approval of biosimilar
medicines; since IAPO’s 2006 Briefing Paper, there have been many developments in their regulation worldwide.
Key questions for regulators that should be answered when considering the approval of a biosimilar medicine:
10
¢
Has data for all the steps in a comparability exercise been provided (quality, non-clinical and clinical)?
¢
Has testing for potential immune reactions been carried out?
¢
Has a plan to manage risk following approval been described?
¢
Has a pharmacovigilance plan been put in place to detect adverse effects?
2006
2007
2008
2009
First biosimilar
approved in
European Union
2010
Adoption of US
legislation for
biosimilar approval
2011
2012
EMA
Guideline for
biosimilar mABs
Figure 3. Key milestones for biosimilar medicines regulators [mABs = monoclonal antibodies]
The rest of the world: The European Union regulatory framework and WHO guidelines have proved to be useful models
for biosimilar medicine regulation and have helped many countries around the world in developing their own regulatory
frameworks. As shown in Figure 4, many countries have developed or are in the process of developing frameworks and
guidelines for the development and approval of biosimilar medicines.
“
It is widely accepted that the WHO, EMA and FDA guidelines should provide a strong
and complete basis for approving biosimilar medicines. However, while some regulatory
authorities follow the EMA or the WHO guidelines as a reference, not all guidelines
across the world meet all of the WHO requirements (such as a full comparability exercise),
potentially compromising patient safety.
”
It is widely accepted that the WHO, EMA and FDA guidelines should provide a strong and complete basis for approving
biosimilar medicines. However, while some regulatory authorities follow the EMA or the WHO guidelines as a reference,
not all guidelines across the world meet all of the WHO requirements (such as a full comparability exercise), potentially
compromising patient safety. Similarly, there is concern that in some developing countries, the approval process and the
post-approval quality control need further development. This is discussed further on pages 20–21.
11
2002
2003
2004
EU
Legal
Pathway
2005
Guideline
development
2006
2007
2008
2009
2010
2011
2012
2013
EU
Overarching
Guidelines
AUS
TUR
KOR
CAN
ARG
USA (draft)
EU
Revised
Guidelines*
MYS
JPN
ZAF
MEX
COL (draft)
TWN
SIN
BRA
CUB
JOR (draft)
The EMA published the first biosimilar
regulatory approval pathway for the
EU member states
The WHO guidelines aim to provide a set of globally acceptable
principles for the approval of biosimilar medicines that can be used as
a reference for countries developing biosimilar pathways across
the world
EU = European Union
WHO = World Health Organization
*
Update to the 2006 guidelines; post-consultation updates pending at the time of publication
†
Update to the 2006 guidelines; in consultation until November 2013
WHO
SAU
IRI
THA (draft)
IND
EU
Update to
Quality Issues
Guideline
EU
Non-clinical
and Clinical
Guidelines†
PER
Figure 4. Global biosimilar guideline/regulation development
[Adapted from timeline provided by Amgen. Data source: publically available information from national health authorities and WHO regulatory guidelines]
To find out if or how biosimilar medicines are regulated in a particular country, contact their national drug
or medical regulatory agency or authority. This information should be available online from that country’s
relevant ministry or department of health.
What categories of biosimilars are currently available?
In the European Union, there are currently four categories of biosimilar medicines marketed. These are human
growth hormones (somatropin), granulocyte colony stimulating factors (filgrastim), erythropoietins (for red blood cell
production) and monoclonal antibodies (infliximab) (see Appendix for more details).25
Biosimilar medicines are available in highly regulated countries such as Japan and Australia. The United States is yet to
approve a biosimilar medicine. It must be noted here that across the world, there are a number of biological medicines
available which are called ‘biosimilars’. However, these biological medicines may have not necessarily have been
through a stringent regulatory process, and completed all the steps for approval, as detailed by the WHO or EMA, to be
called a biosimilar.26 These products have a number of names globally but are often called ‘non-comparable follow-on
biological products’ or ‘non-innovator follow-on biological products’.26,27 The quality of these products can vary greatly
with different implications for patient safety.28
What has been the impact of biosimilar medicines?
While the development of generic medicines has seen cost reductions of between 80–90%, the availability of biosimilar
medicines is comparatively expected to bring cost reductions of between 15–30%.29 This is due to high development
and manufacturing costs and long development times. The development process can take between five and nine years
(compared to three years on average for generics)30 and can cost between US$75–250 million (compared to US$2–3
million for generics).31
has fallen. In the United Kingdom, the availability of a biosimilar filgrastim has allowed doctors to use this as primary
prophylaxis, i.e. from the first chemotherapy cycle to prevent infection and readmission to hospital.8
The biosimilar medicines market is at early stages across the world. Currently, the European Union accounts for 80%
of spending on biosimilar medicines. However, even within Europe there has been differing market penetration and
uptake. Currently, Germany accounts for 34% of spending on biosimilars, and France accounts for 17%; however
spending in other countries such as the United Kingdom is increasing.32 A project set up by the European Commission
to define the conditions needed for adequate access and uptake of biosimilar medicines found that within the three
markets for the three types of biosimilar medicines available (growth hormone, erythropoietin and granulocyte colony
stimulating factor), there was varied volume and growth.33
The spending and uptake of biosimilar medicines depends on a number of factors such as local pricing, reimbursement
policies, the influence of different stakeholders and perceptions of biosimilars.32 It has been argued that differences in
price between the reference product and biosimilar are also likely to be affected by the size of their market share, with
price differences being higher where biosimilars have a higher market share.8
Since their development in the 1980s, biological medicines have developed into a US$138 billion market (2010)
worldwide.32 As more biosimilar medicines are developed such as the monoclonal antibodies (see following section),
the potential for growth in the global biosimilars market over the next 10–20 years is huge. In the first half of 2011,
sales of biosimilars reached US$378 million; by 2015 it is predicted that sales will reach between US$1.9–2.6 billion.32
It has been estimated that there has been a 23% growth in sales of biosimilars since 2011 across seven major markets
including Europe and the United States.34 With the US publishing its guidelines for biosimilar development in 2012, it
has been predicted that by 2020 the US will have a biosimilars sector worth between US$11–25 billion.32
What next for biosimilars?
It is predicted that as patents expire over the next five years for a number of biological medicines with high sales, the
development of biosimilar medicines for the treatment of cancer, diabetes, rheumatoid arthritis and multiple
sclerosis will be seen.32
It is predicted that the monoclonal antibodies (mABs) will comprise a large proportion of the biosimilars market.
Monoclonal antibodies are highly specific antibody proteins and can be developed to target a specific molecule very
precisely. The development of monoclonal antibodies has allowed the development of treatments for a number of
cancers, cardiovascular diseases, autoimmune diseases and more powerful diagnostic tests. Due to the great complexity
of antibody molecules, the EMA decided that specific guidelines for biosimilar mABs were required, and in 2012
the EMA adopted the final guidelines for biosimilar monoclonal antibodies. In June 2013 the EMA approved two
monoclonal antibody biosimilars of infliximab (for the treatment of rheumatoid arthritis).35,36 Now that guidelines for
mABs exist, It is expected that a number of biosimilar monoclonal antibodies will become available on the European
market and worldwide in the coming years.
Biosimilar insulins are also expected to enter the insulin landscape in the coming years as the patents for major insulin
products begin to expire.37
As more biosimilar medicines become available, there will be opportunities for manufacturers to improve packaging
and administration methods for these medicines. For example, one biosimilar filgrastim currently being produced
comes with a ‘Patient Support Kit’ which allows patients to self-administer the medicine at home.38 This could allow for
biosimilar medicines to be used in primary care settings or in the home, instead of hospital settings, and could improve
adherence to medication.
However, overall savings are likely to be substantial, especially as more biosimilar medicines become available on
markets across the world. It has been estimated that if biosimilar versions of just seven expensive reference biological
medicines were available in Europe, savings of up to €2 billion could be seen, freeing budget for other areas of the
health system.19 Chemotherapy treatment for patients with cancer can cause a lowering of white blood cell count in
the body (white blood cells are essential in helping the body fight off infection). This can be prevented and treated
with filgrastims such as Neupogen (a reference product), which stimulates white blood cell production. Due to its high
price, Neupogen is often used as secondary prophylaxis i.e. after chemotherapy has begun, once white blood cell count
12
13
Part two: What matters to patients
In December 2012, IAPO held an online consultation with its membership to understand the level of awareness of
biological and biosimilar medicines, their regulation and use, and what the most important issues and concerns were
for patients’ organizations. A total of 35 responses were received. Following the online consultation, a number of indepth, follow-up interviews were carried out with patients’ organizations worldwide.
Additionally, a range of stakeholders were consulted about the issues they thought were important regarding biosimilar
medicines. These stakeholders included biological medicine and biosimilar manufacturers, regulatory agencies, industry
trade associations, medical associations and academics.
A full list of those interviewed can be found on page 29. The following sections outline the main issues identified by
patients’ organizations in the online consultation and also during interviews, taking into account opinions of other
stakeholders and additional issues identified.
Findings of the online consultation
¢
There was varied awareness of biosimilar medicines among respondents (see Figure 5). The high proportion of
respondents with little or no awareness of biosimilar medicines may explain the lower than usual response rate to
an IAPO consultation.
21%
31%
¢High awareness
¢Some awareness
¢Little awareness
17%
31%
¢No awareness
Figure 5. Awareness among respondents of biosimilar medicines
¢
54% of the patients’ organizations that responded represented patients who were currently using biological
medicines for treatment of their disease.
¢
20% of the respondents represented patients who were using biosimilar medicines.
¢
60% of organizations who responded did not know whether their patients were using biosimilar medicines.
¢
The majority of respondents had some (32%) or no awareness (36%) of how biosimilar medicines were regulated in
their country or region (see Figure 6).
15
18%
36%
¢High awareness
¢Some awareness
32%
14%
¢Little awareness
¢No awareness
Figure 6. Awareness among respondents of how biosimilar medicines are regulated
¢
The most important issues for patients regarding biosimilar medicines were identified by patients’ organizations as:
• safety (side effects, reliability, regulation)
• patient information and education regarding biosimilar medicines
• switching between biosimilar medicine and reference product (prescription transparency)
• how biosimilars are monitored and tracked (pharmacovigilance)
• availability and access to biosimilar medicines.
¢
The majority of patients’ organizations that responded to the consultation were based in Europe, North America or
Australia. Their levels of awareness were varied. Respondents from Latin America tended to have some awareness
on the topic whereas those from Africa had no awareness at all. There was only one respondent from the Asia
Pacific region. They had no awareness of biosimilar medicines.
What do patients need to know about the safety of biosimilar medicines?
Ensuring the safety of biosimilar medicines is an important issue for patients’ organizations. Safety includes a broad
range of issues from how biosimilars are defined and named, to their ability to cause immune reactions, regulation and
pharmacovigilance. These are discussed in detail below.
Could there be adverse effects?
Biological medicines, including biosimilar medicines, have the potential to cause an immune reaction in the body. This is
an ongoing concern for both patients and doctors.9
The consequences of adverse effects of biological medicines can range from having no clinical effect on the body at all,
to much more serious adverse effects due to a loss of efficacy or neutralisation of the medicine, making the medicine
less effective or completely ineffective.4,39 The most common effect is a loss of efficacy, i.e. the medicine does not
work as well as it did before, which can lead to general immune reactions such as allergic reactions or anaphylaxis.39
In some cases antibodies produced in the body neutralise the medicine so it stops working completely which can be
dangerous.39 In other cases, autoimmunity can occur when antibodies which are produced to neutralise the protein in
the medicine become confused and neutralise the body’s own protein as well.13,40
Whether a biological medicine, including a biosimilar medicine, causes an immune reaction depends on a number of
factors:5,39
¢
the stage of the disease
¢
drug-related factors such as aggregates, impurities or contaminants
¢
patient-related factors such as the age and sex of a patient
¢
factors relating to treatment such as other drugs that are being used or how they are administered.
“
The potential of a biosimilar medicine to produce an immune reaction has to be assessed
in great detail during its development...
16
”
The case of EPREX
Patients on erythropoietin (EPO) treatment, a biological medicine, can develop pure red cell aplasia (PRCA), a type
of anaemia, caused by the neutralization of the body’s own erythropoietin. Between 2000 and 2002 there was
a sharp increase in the number of cases of PRCA in patients. These cases were associated with the development
of a neutralising antibody to the erythropoietin being given to patients, which also neutralised the body’s own
erythropoietin as well. It was eventually discovered that this immune reaction and the increase in PRCA cases
was in fact due to a small manufacturing change in the formulation of a well-known and widely used biological
medicine called Eprex.13
Although Eprex was not a biosimilar medicine but an original biological medicine, in making a change to the
manufacturing process, the Eprex case clearly shows how a small change can affect the ability of a biological medicine
to produce an immune reaction. These reactions are difficult to predict, they may arise after the patient has been taking
a medicine for a long time, and they can continue after the patient has stopped taking the medicine.19,41
The factors described above mean that the potential of a biosimilar medicine to produce an immune reaction has to
be assessed in great detail during the development of the biosimilar medicine, before it is made available to patients.
Although there are methods that can help predict this before clinical trials,42 these are often insufficient, therefore
clinical studies are essential. Sometimes if it is known that a certain immune response is rare in the reference product,
therefore unlikely to be sufficiently captured in a clinical study before being made available to patients, further clinical
studies may be necessary after the medicine is being used to treat patients.9
A recent consensus information document published by the European Commission states that at the time of
publication no specific safety concerns had been identified for approved and marketed biosimilar medicines by the
Committee for Medicinal Products for Human Use (CHMP) and the CHMP Pharmacovigilance Working Party (PhVWP)
of the European Medicines Agency.18 Furthermore, a recent study, which used all the available safety evidence for
two approved biosimilar erythropoietins (in Europe), found that both had similar safety profiles to each other with
neither being more or less safe. They also found that, statistically, the incidence of known adverse effects for the two
biosimilars was not higher than what is known about erythropoietins in general.43
What systems are in place to monitor medicine safety?
“The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or
any other drug-related problems” is defined as ‘pharmacovigilance’ as defined by the WHO.44 Pharmacovigilance
is critical in ensuring the safety of all medicines, especially biological drugs. As all biological medicines can potentially
cause an immune response after approval, surveillance and monitoring are absolutely essential to track any adverse
effects caused by the medicine.6,13
Clinical trials include a limited number of patients and are conducted over a limited time period.45 Some adverse effects,
however, may not be seen until a larger number of people have received the medicine and this may be after the end of
the trial. Furthermore, clinical trials may not reflect how a medicine is used in a real world setting.
All pharmaceutical companies are required to have pharmacovigilance systems in place for every drug that they
manufacture. In Europe and the United States, pharmacovigilance plans and plans to manage risk are compulsory
before all drugs, including biosimilars, can be made available to patients.40 A plan to manage risk includes
pharmacovigilance information on what is known about the safety of the biosimilar medicine before availability, how
information will be gathered on safety once available to patients, and how risk will be managed if an adverse drug
reaction occurs.46 In order to gather information about the safety profile of the biosimilar medicine, large studies may
be conducted to detect any adverse events that happen over time.19
Both reference products and biosimilar medicines can change over time due to manufacturing or environmental
changes. These changes may affect how the medicine works. This highlights the importance of good monitoring and
pharmacovigilance. It is important that manufacturers carefully monitor their biological products to effectively control
changes over time.
17
IAPO’s online membership consultation on biosimilar medicines revealed that:
¢
50% of respondents had some to high awareness of the pharmacovigilance system in their country
¢
33% had little awareness
¢
19% had no awareness at all.
However, a number of patients’ organizations from both developed and developing countries highlighted the
importance of a strong pharmacovigilance system and the lack of it in their countries:
“We need to have systems in place to capture information and study it. The question is of labelling and tracking. We
need to know what is causing an adverse effect.”
Marc Boutin, National Health Council, USA
Weak pharmacovigilance systems were highlighted as a problem by other stakeholders:
“There is a real problem with pharmacovigilance here [Latin America] – the reporting of adverse effects is very small
especially in countries where there is no biosimilars regulation at all.”
Dr Ricardo Garcia, CLAPBio, Brazil
Stephen Murby from the Consumer Health Forum of Australia explained that in Australia, patients experiencing adverse
effects often do not report them, especially if they subside over one or two weeks, and that general practitioners may
treat the adverse effect that occurs but not necessarily report it. He also explained that how biosimilar medicines are
defined might also create problems:
“A real fundamental issue is that we tend to use the term generic to include biosimilars which is problematic as we
aren’t teasing out all of the consumer-related issues that may occur.”
Stephen Murby, Consumer Health Forum of Australia
He stressed that as more biosimilar medicines become available globally, patients’ organizations must take the
opportunity to advocate for improved pharmacovigilance systems worldwide, and for the development of a more
unified adverse effect reporting system globally.
What’s in a name – what should patients report in case of an adverse effect?
Pharmacovigilance depends on being able to track and trace biological and biosimilar medicines. This depends on
whether doctors, pharmacists and patients can differentiate between two medicines.3 Manufacturers of medicines can
apply to the WHO for an International Non-Proprietary Name (INN). INNs facilitate the identification of pharmaceutical
substances or active ingredients in medicines.47 Each INN is a unique name which is different to the brand name in
order to prevent confusion and ensure patient safety.
The same INN can be used for more than one medicine. For example, in Europe there are three biosimilar
erythropoietins available whose brand names are Binocrit, Epoetin alfa Hexal and Abseamed. The INN for all three of
these biosimilar erythropoietins is ‘Epoetin alfa’. The originator medicine for these biosimilar medicines was Eprex,
whose INN is also ‘Epoetin alfa’. The INN for a new biosimilar can be the same as the reference product and the
multiple brands of the biosimilar itself.
Multiple medicines having the same INN could cause problems with traceability. If doctors or pharmacists use only
the INN when prescribing a biological or biosimilar medicine, and multiple products have the same INN, it will not be
known exactly which medicine the patient is being given. Therefore if an adverse effect occurs it is not clear which
medicine caused it.3 This can be problematic in ensuring patient safety.
18
Patient safety can also be affected by the common prescribing practices in a country, for example, some doctors tend
to prescribe medicines using the brand name and others may use the INN only. The Medicines and Healthcare Products
Regulatory Agency (MHRA) of the United Kingdom recommends that it is good practice to use the brand name when
prescribing all biological medicines including biosimilars and states that even though some reference and biosimilar
medicines will have the same INN, this does not mean that they are identical.48
This issue has been widely recognized by all stakeholders in the field and a number of different suggestions have been
made to ensure patient safety and accurate tracking and traceability.
Biosimilar medicines should be prescribed by their brand name and not just the INN so it is clear exactly which
medicine a patient is taking. In Europe much work has been done on this issue to ensure strict pharmacovigilance and
identification. The EMA recommends that to prevent confusion, the brand name, manufacturer’s name and the
batch number should be used when reporting any adverse effects caused by any given biological medicine.40
Most recent efforts to strengthen pharmacovigilance in the European Union (EU) have led to the implementation of
a new Pharmacovigilance Directive (2010/84/EC) in 2012. This has become a law and has been implemented in all
EU Member States. It is congruent with EMA recommendations, requiring brand name and batch number reporting,
and allows patients to report any adverse effects directly to local authorities.49 In Europe, a recent study exploring the
traceability of approved biological medicines revealed correct recognition of 96.2% of biosimilar medicines available in
Europe, during adverse effect reporting.50
In Europe, where patients are able to report adverse events directly, the study found that 40% of direct reports by
patients did include the batch number of medicine, highlighting the important role of patients in ensuring that the
biological medicines are traceable.50
How are medicines prescribed in your country? Patients should ensure that when they are prescribed a
biological or biosimilar medicines they know the brand name and where to find the batch number of their
medicine.
What are patients being prescribed?
Knowing what they were being prescribed and switching between medicines were identified as causes of concern for a
number of patients’ organizations. This was also mentioned by some regulators and industry representatives.
Most generic medicines are interchangeable with the original branded product, i.e. a patient could be swapped from
one to the other with no difference in effect.6 This is because generic medicines are bioequivalent with their original
medicine and therefore it does not matter which drug a patient is receiving. As generic medicines are interchangeable,
they can be substituted for the original branded medicine at the pharmacy level by a pharmacist without having to
inform the doctor or the patient.3
Key definitions
Interchangeability: The practice of changing one medicine for another that is expected to achieve the same clinical effect in a
given clinical setting and in any patients, or with the agreement of the prescriber.
Substitution: The practice of dispensing one medicine instead of another equivalent and interchangeable medicine at the
pharmacy level without informing the prescriber.
Automatic substitution: The practice whereby a pharmacist is obliged to dispense one medicine instead of another
equivalent and interchangeable medicine due to national or local requirements without consulting with the prescriber.
Switching: Decision by the treating physician to exchange one medicine for another medicine with the same therapeutic
intent in patients who are undergoing treatment.
19
Substitution and automatic substitution can occur to save costs. It can also be linked to reimbursement, as some health
insurance companies will only cover the costs of the cheaper generic drug as opposed to the branded drug.3,40
Some patients’ organizations explained that there was poor regulation of biosimilar medicines in their countries which
was a concern for patient safety.
Biosimilar medicines are similar to their originator product in terms of quality, safety and efficacy. Therefore, whether
biosimilars should be considered as interchangeable is an area of ongoing debate.
“Regulation is a problem. There is no global policy. There is no regulation here and no pharmacovigilance studies.”
Eva Maria Ruiz de Castilla, Esperantra, Peru
Fears around automatic substitution and switching of patients from the reference product to the biosimilar, or between
different biosimilars, are based on the issues of tracing and reporting.
“Many regulatory agencies in different countries follow the guidance of their government, and the government
wants to reduce cost, so they might not have regulation in place. Politics can’t come before technical issues and put
patients at risk.”
Dr Dirceu Raposo, Abrale, Brazil
If a biosimilar medicine has been substituted for the reference product and the doctor does not know this, it can cause
problems with reporting if an adverse effect occurs. For safety monitoring, doctors should be fully aware of the exact
medicine their patient is taking. Additionally, immune reactions to a biological medicine can happen after a patient
has been using the medicine for a long time. If automatic substitution or repeated switching between medicines has
occurred during treatment it may be difficult to tell which product is responsible for the adverse effect.3,40,51
“I do not support automatic substitution because we strongly believe that the physician should be the decisionmaker as he knows the patient best, secondly it will be difficult to trace what medicine the patient actually got and
how can you do proper pharmacovigilance then?”
Thomas Schreitmuller, Roche
The Chair of the Biotherapeutics Group of the International Federation of Pharmaceutical Manufacturers & Associations
(IFPMA) highlighted that this is not just a matter of pharmacovigilance. Ensuring transparency in prescription and
dispensing of medicine is important, and patients should know what medicine they are taking.
Patients’ organizations were concerned about switching once a biosimilar version of a medicine is made available
to patients. Many stakeholders thought it was appropriate for a new patient starting therapy for the first time to be
started on the biosimilar version of the medicine (if available) they have been prescribed. However, most patients’
organizations agreed that a patient being treated with a biological medicine should not be switched onto the biosimilar
version without the knowledge of the patient, or the patients’ clinician.
“Hopefully the availability of a biosimilar medicine won’t compel people on biologics to switch, but for new a
patient who initiates biologics, a cheaper alternative to the original medicine is a great benefit.”
Marc Boutin, National Health Council, USA
In Europe, the EMA does not assess interchangeability or automatic substitution; this is decided individually by each
Member State.15 A number of European Member States have provided guidance and a number have created legislation
to prohibit automatic substitution without the knowledge of the prescriber.52
The WHO currently does not provide guidance on interchangeability or automatic substitution in its guidelines for the
approval of biosimilar medicines, and again this decision must be made by each country individually.
“
Biosimilar medicines are similar to their originator product in terms of quality, safety and
efficacy. Therefore, whether biosimilars should be considered as interchangeable is an area
of ongoing debate.
”
When is a biosimilar not a biosimilar?
Good regulation of all medicines is essential to ensure patient safety, and biosimilar medicines have a different
regulatory pathway to a new biological medicine or to a generic medicine. A biological medicine can only be
considered biosimilar if it has gone through a strict regulatory process, as described in the EMA or WHO guidelines. It
is widely accepted that any medicine claiming to be biosimilar that has not been approved through a strict regulatory
pathway could be compromised in terms of quality, safety and efficacy.
20
Globally, the regulation of biosimilar medicines has improved vastly since IAPO’s first briefing paper was launched
in 2006. Many countries have developed or are in the process of developing laws and guidelines. It is important to
consider whether these laws and guidelines have been developed according to international standards, i.e. those of
the WHO. Dr Ricardo Garcia of CLAPBio, the Latin American Centre for Biological Research, explained in a recent
presentation, that although many countries in Latin America have issued guidelines, these may not cover all the
requirements for biosimilar approval, such as all the steps in a comparability exercise.53 Countries may have regulation
in place, but there can be differences in how the steps in the regulatory process are interpreted.27
“For the developing world the problem is that the approval procedure for biosimilar medicines is not as strict and
well-established as in the European Union and the United States, you have to have quality control after approval as
well. There is no real high-quality approval procedure so people may not know what they are buying.”
Dr Ursula Gundert-Remy, German Medical Association
Some countries such as Brazil have used the WHO guidelines as a basis for their own regulatory guidelines, but with
some differences. The Brazilian guidelines include two pathways for approval with different levels of data required for
approval.54 This is to encourage local production of biological medicines and reduce the cost of these medicines.55
It is generally agreed that a medicine can only be called biosimilar if it is authorized on the basis of a full comparability
exercise that is described in the WHO guidelines.27 However, across the world a number of medicines exist which are
copies of an original biological medicine that have not been authorized on the basis of a full comparability exercise, and
so cannot be called biosimilar. These are generally referred to as ‘non-comparable follow-on biological products’.26
For example, a medicine called Reditux, which is a copy of the monoclonal antibody rituximab used for the treatment
of rheumatoid arthritis and some cancers, has been available in India since 2007.56 It cost approximately half of the
original medicine’s price.57 However, its approval has been based on less evidence than is required for approval in
Europe or the United States, and it is not known if it has undergone clinical comparability trials.32,58
There are concerns about the quality and safety of medicines whose approval has not followed a strict regulatory
pathway as described by EMA and WHO.59 Although some may be high-quality copies of the original biological
medicine, others may be sub-optimal and poor quality.
“The [non-comparable follow-on biological medicines] may be sub-optimal products and are available around the
world especially in Latin America, Asia and the Middle East. Often if the real reference product is available in a
country as well, patients may not know which they are receiving, due to prescription by INNs – and if you can’t
identify the real biosimilar from the non-comparable follow-on biologic then you can’t identify which product is the
source if a side effect occurs.”
Fermin Ruiz de Erenchun, Biotherapeutics Group, International Federation of Pharmaceutical
Manufacturers and Associations
As more countries begin to develop regulatory pathways for biosimilar medicines, the question arises as to what to
do with non-comparable follow-on biological products that were approved before the pathways were developed. For
example, Reditux, mentioned above, was approved in India in 2007. However, India only released its guidelines on
similar biologics in 2012.60
21
“Countries such as Peru, Chile and Colombia approved non-comparable follow-on biologic products before there
was any regulation. Now we have to look at what happens to the product now that there is regulation. I think they
should ask the manufacturers to present all the data that is needed [quality, non-clinical and clinical] and give them
a time limit to present the information.”
Dr Ricardo Garcia, CLAPBio, Brazil
Although there has been much progress in terms of regulation, much work still needs to be done to harmonise global
biosimilar medicine regulatory standards with those stringent regulatory agencies such as EMA, WHO or US Food and
Drug Agency (FDA). This is to ensure that all patients receive products that are of high quality, safe and efficacious.
¢
¢
A biological medicine can only be called biosimilar if it has undergone strict regulation and full biosimilar
comparability testing including quality, non-clinical and clinical studies.
Adverse effects are expected for all medications, chemical or biological, however strong pharmacovigilance
systems and plans to manage risk are critical in ensuring patient safety.
Who can access biological and biosimilar medicines?
Poor access to biological and biosimilar medicines was highlighted in the online consultation and interviews as an issue
by patients’ organizations in developed and developing countries.
“In low-income countries like Peru, we have doctors who treat with biosimilars and are very happy, but the people
in charge of the budget are not interested to continue using these medicines as they are too expensive. Sometimes
biosimilars are not on the list of approved medicines. It is very difficult to get access. So even if the patient gets the
right diagnosis, they won’t get the medicine. For me, we need to advocate for more access – show that treatments
with biosimilars are working.”
Eva Maria Ruiz de Castilla, Esperantra, Peru
Barriers to access to biological and biosimilar medicines that meet standards of EMA, WHO and FDA include:
¢
high price of medicines
¢
poor knowledge and understanding by governments, clinicians and patients of what biological medicines are
and their therapeutic value
¢
poor or lack of regulation of biological and biosimilar medicines
¢
low or lack of political will to ensure access
¢
more complex administration methods
¢
poor diagnosis, screening and testing.
In their Frequently Asked Questions document, the European Generics Association (EGA) explain that, as well as
agreeing prices and reimbursement, it is important to “ensure that clinicians and patients fully appreciate the benefits
of using biosimilar medicines as part of their practice and treatment. Access for patients to biosimilar medicines is not
automatic; it requires that proactive steps be taken by all relevant stakeholders”.61
Cultural and geographic factors also affect the availability of biosimilar medicines. For example, in some developing
countries or regions generic prescribing and dispensing practices are not widely accepted. This means that more
expensive brands are often prescribed and dispensed rather than cheaper versions that could enable more patients to
access them.41
Interviews with patients’ organizations also revealed that in many developing countries the availability and regulation
of biological and biosimilar medicines is a political issue rather than a technical issue. Governments will often provide
the cheapest alternative of a medicine, regardless of whether it is a biosimilar medicine or a non-comparable follow-on
biological medicine. Although many patients’ organizations explained that access to medicines should not be decided
purely on cost reductions, it was also highlighted that patients are willing to take any medicine available to them. In
settings where access to medicines is limited and a patient has a life-threatening illness, it is very likely that they will
take a medicine offered to them even if it is of low quality. This raises the question: is some access to potentially lowquality biological medicines better than no access at all?
Additionally, Eva Maria Ruiz de Castilla from Peru explained that lack of education and understanding of biological and
biosimilar medicines amongst all stakeholders was a barrier to access in Peru. She explained that the authorities see
all biological medicines, including biosimilar medicines, as too expensive and do not differentiate between the two.
She explained that patients’ organizations need to advocate for access to biological and biosimilar medicines through
unbiased education of those in charge of healthcare.
Even though they are often cheaper than their originator product, biosimilar medicines are still unaffordable for many
developing countries. It is important that pharmaceutical companies that consider different approaches to pricing are
essential for markets in developing and developed countries to ensure access to biological and biosimilar medicines.
Dr Ricardo Garcia from CLAPBio in Brazil noted that there should be more local investment in technology. This will
enable countries to develop their own high-quality, safe and efficacious biological and biosimilar medicines.
What information and support is available for patients?
As for any medicine, being able to make a fully informed decision to take or prescribe a biological or biosimilar
medicine is important for patients, doctors, nurses and pharmacists. Patients must be involved in deciding what
treatment to pursue with their healthcare team. Patients need to be aware of and understand the medicine they are
taking, the potential reactions they may experience, and how it will be administered. They must also monitor their
response to it.
Marc Boutin from the National Health Council in the United States said that in the US, although biosimilars can reduce
costs, in most cases this reduction does not necessarily benefit the patient but rather the insurance company or payer.
Out-of-pocket payments for biosimilar medicines would still remain quite high. Durhane Wong-Rieger from Consumer
Advocare Network in Canada stated that the availability of a biosimilar growth hormone in Canada had not necessarily
increased access to the medicine for patients:
A significant lack of knowledge about biosimilar medicines was revealed in consultations with patients’ organizations.
Many patients had not heard about them, including those that may have been prescribed to them.
Lack of awareness of biosimilars among doctors was also described. In one study, one-third of Brazilian rheumatologists
surveyed did not know what a biosimilar medicine was.62
“This is really sad as a lot of people don’t qualify for the biosimilar growth hormone either as their endogenous
growth hormone is not low enough. The barrier hasn’t got anything to do with the biosimilar itself.”
Durhane-Wong Rieger, Consumer Advocare Network, Canada
The reduction in cost of a biosimilar medicine can depend on how the price and reimbursement of a medicine is
decided in a particular country and the price competition between products that these access conditions support.40
22
In Europe, each country independently decides on the therapeutic value of a medicine, its price and how it will be
reimbursed.41
“Biosimilars are not really a big issue here. We are still discussing generics! It is a very new topic in the region.”
Edith Grynszpancholc, Fundación Natalí Dafne Flexer, Argentina
A need for accurate and unbiased information was identified by patients’ organizations. They explained that there was
either a complete lack of information, or that the information available was unclear. Lack of accurate information about
what biosimilars are and which diseases they are used to treat led to confusion among patients, explained Eva Maria
23
Ruiz de Castilla from Esperantra, Peru. She said patients need to be educated that biological and biosimilar medicines
were not available for all diseases. This highlights the need to improve efforts on developing health literacy worldwide.
Misinformation and incorrect perceptions of biosimilar medicines was cited as an issue by a number of stakeholders.
Joerg Windisch, Chief Scientific Officer, and Mark McCamish, Global Head of Biopharmaceuticals Development
at Sandoz thought that there is biased information available released by originator companies that had led to
misperception around biosimilar medicines. They felt that this may have led to unsubstantiated fears regarding safety
and quality among the physician and patient community in prescribing and using biosimilars respectively, and could be
likely a barrier to access and uptake.
Should patients be involved?
Patients should be involved and engaged in issues relating to biosimilar medicines. To play an active role, patients have
a right to inform themselves with evidence-based and neutral information.
“Patients should be active and organized and look for technical and safe information without a political agenda.”
Dr Dirceu Raposo, Abrale, Brazil
Patients also have a role in advocating for clear, unbiased and balanced information where unavailable.
It is clear from interviews with patients’ organization representatives that there is a need for transparent and accurate
information from a variety of sources.
For more information on how patients’ organizations can get involved, please see the ‘What patients’
organizations can do’ booklet in the Toolkit.
“Is there any place where one can see what this medicine is? Is there anywhere one can see where and how the
medicine was approved? We need to get accurate information. It is not desirable but the only information we get is
usually from pharmaceutical companies.”
Edith Grynszpancholc, Fundación Natalí Dafne Flexer, Argentina
“There is a knowledge gap around the world and a need for government training and support. There needs to be a
concerted effort from all and patients can advocate for this.”
Fermin Ruiz de Erenchun, Biotherapeutics Group, International Federation of Pharmaceutical
Manufacturers and Associations
A number of stakeholders interviewed also explained that patient information and education was critical in ensuring
that patients feel comfortable with and accepting of biosimilar medicines.
“Firstly the emerging science is complex, secondly, economically the patent and exclusivity rights are complex, thirdly
and most importantly patients and healthcare practitioners have to learn about a completely new paradigm
[biosimilar medicines] and have faith in it.”
Dr Rachel Sherman, US Food and Drug Administration
There need to be systems in place for patients to ask questions about their medicines and discuss any concerns. Many
doctors are hesitant to consider biosimilar medicines as a treatment option for their patients due to fears regarding
their safety, quality, efficacy and interchangeability.9
Doctors and nurses also need unbiased and current information about the complex science and regulatory processes
of biosimilar medicines not only to guarantee access (if available) but also safety. It has been highlighted that a lack of
awareness and education among nurses could lead to medication errors and delays in therapeutic gain for the patient.63
All stakeholders have a role in providing information and there is great potential for joint efforts. Healthcare companies
and associations, regulators, medical professionals and scientific researchers can bring together technical, scientific and
medical data. Patients’ organizations and patients themselves can bring expertise on how to best present information,
communicate risks and to increase the involvement of patients in decisions which affect their health.
An example of this is a consensus information document called ‘What you need to know about Biosimilar Medicinal
Products’, published on the European Commission’s website in 2013.18 This document was developed with input from
a variety of stakeholders including patients’ organization representatives, health professional associations, generic
medicine associations and pharmaceutical trade associations, and European Union Member States.18
Patients’ organizations and other stakeholders stressed that regulatory bodies also need education and training.
Dr Ricardo Garcia of CLAPBio (the Latin American Centre for Biological Research) in Brazil explained that their mission
was to promote discussion and learning around the regulation of biological and biosimilar medicines. He explained that
recently they had provided comments on the first draft of the Colombian regulatory guidelines for biosimilar medicines
and were subsequently invited by the Colombian government to provide an education and training session on the issue
for their staff. This is an excellent example of collaboration between regulatory bodies and research centres in order to
promote good education and regulation of biosimilar medicines.
24
25
Conclusions and recommendations
This Briefing Paper provides a detailed overview of what biological and biosimilar medicines are, how they are
developed and regulated, and how they are used by patients. It presents important issues as identified by patients’
organizations and other stakeholders that were interviewed. These included the safety of biological medicines, how
they are regulated and monitored, how they are prescribed and dispensed, as well as who can access them and what
information and support is available to patients.
Biological medicines have revolutionised the treatment of many diseases and have benefited millions of patients
worldwide. In the coming decade we expect a large number of biosimilar medicines to become available around
the world. These will provide alternative medicines for patients, usually at lower cost, and will increase options for
doctors, patients and healthcare systems in general. Ensuring access to high-quality, safe and efficacious biological and
biosimilar medicines depends upon a number of things:
¢
¢
¢
¢
¢
Educating patients, doctors, governments and ministers of health about what these medicines are and what their
potential therapeutic and social impact could be is essential to increase commitment to making biological and
biosimilar medicines available where they are not yet, and if they are, to ensuring that they are actively prescribed to
patients.
Patients need to ensure that they know the brand name and batch number of the biological medicine they have
been prescribed, as well as how and where to report any potential adverse effects.
Where biological and biosimilar medicines are available for patients or are becoming available, stringent regulatory
guidelines based on those of the EMA, WHO or FDA and robust pharmacovigilance and adverse effect monitoring
systems are key to ensuring patient safety.
In countries where copies of biological medicines were available before stringent regulatory pathways were put into
place, governments must consider what do to with these medicines which may potentially be of lower quality and
unsafe.
As more biological and biosimilar medicines become available worldwide, this presents an opportunity to focus
upon developing, strengthening and unifying pharmacovigilance systems worldwide.
More information about how patients’ organizations can advocate for access to biological and biosimilar
medicines, better regulation or pharmacovigilance and tips on education can be found in the ‘What patients’
organizations can do’ booklet in IAPO’s Information and Advocacy Toolkit on Biological and Biosimilar
Medicines.
27
Review process and acknowledgements
This Briefing Paper was developed through a rigorous review process. IAPO received guidance, input and feedback
from patients’ organizations, academics, regulators and other experts during the development of this Toolkit. Further
feedback was received from the 19 participants of IAPO’s Workshop on Biosimilar Medicines, held in Geneva in 2013.ii
IAPO would like to thank everyone involved in the production of this Briefing Paper and the Information and Advocacy
Toolkit on Biological and Biosimilar Medicines that it is part of, including workshop participants, members who
responded to a consultation on biological and biosimilar medicines in December 2012, and the patients’ organizations
and stakeholders that were interviewed during the development of this Briefing Paper. We thank them for sharing their
opinions and giving their time.
IAPO’s Information and Advocacy Toolkit on Biological and Biosimilar Medicines was produced under the overall
direction of Joanna Groves, Chief Executive Officer of IAPO, and Jeremiah Mwangi, Policy and External Affairs Director,
with core project management, research and writing from Yasemin Dil, Research and Project Officer. IAPO would
also like to thank Matt Cann and Éloïse Varin at Postscript Communications Ltd for the design and production of this
Toolkit. We would like to acknowledge the contribution of the following people and organizations who provided
technical information and advice during the development of this Toolkit:
Marc Boutin, Executive Vice President and Chief Operating Officer, National Health Council, USA
Professor Dr Daan Crommelin, Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences
Michael Kinyanjui, Africa Psoriasis Organization, Kenya
Suzette Kox, Senior Director Scientific Affairs, Coordinator of the European Biosimilars Group, sector group of the
European Generic medicines Association
Dr Dirceu Raposo, ABRALE and formerly at ANVISA (National Health Surveillance Agency), Brazil
Professor Huub Schellekens, Departments of Pharmaceutical Sciences and Innovation Studies, Utrecht University
Dr Christian Schneider, Chair of Biosimilar Medicinal Products Working Party, European Medicines Agency (EMA)
The International Association of Pharmaceutical Manufacturers & Associations (IFPMA)
Patients’ organization representatives and other stakeholders interviewed:
Representative of AbbVie
Dr Kenichi Akamatsu, Senior Professional, API Process Development Department, Chugai Pharmaceutical Co. Ltd,
on behalf of Japan Pharmaceutical Manufacturers Association (JPMA)
Marc Boutin, Executive Vice President and Chief Operating Officer, National Health Council, USA
Maria Delfina Tay, President, Procrece Association, Guatemala
Dr Ricardo Garcia, CLAPBio (Latin America Center for Biological Research)
Paul Greenland, Chair of Biosimilars Market Access Group, and Suzette Kox, Senior Director Scientific Affairs,
European Generics Association (EGA)
Edith Grynszpancholc, President, Fundación Natalí Dafne Flexer, Argentina
Professor Dr Ursula Gundert-Remy, Vice President of the Drug Commission, German Medical Association
Virginia Ladd, President and Executive Director, American Automimmune Related Diseases Association
Representative of Merck Serono
Stephen Murby, Governing Board Member, Consumer Health Forum of Australia
Representative of Pfizer
Dr Dirceu Raposo, ABRALE and formerly at ANVISA (National Health Surveillance Agency), Brazil
Representative of Roche
Eva Maria Ruiz de Castilla, Director, Esperantra, Peru
Dr Fermin Ruiz De Erenchun, Chair of Biotherapeutics Groups, International Association of Pharmaceutical
Manufacturers & Associations (IFPMA)
Representative of Sandoz
Dr Christian Schneider, Chair of Biosimilar Medicinal Products Working Party, European Medicines Agency (EMA)
Dr Rachel Sherman, Associate Director of Medical Policy, Centre for Drug Evaluation and Research, United States Food
and Drug Administration (FDA)
Professor Arnold Vulto, Founder of Generics and Biosimilars Initiative Journal (GaBI)
29
Durhane Wong-Rieger, Consumer Advocare Network, Canada
Glossary
Where possible, this glossary contains definitions from the World Health Organization (WHO) or European Commission.
Active substance: Active ingredient or molecule which goes into a specific medicine and which provides this medicine
with properties for treating or preventing one or several specific disease(s).
Adverse effect: Any unintended or unfavourable event following the administration of a given medicine. An injury
related to medical management, in contrast to complications of disease. Medical management includes all aspects of
care, including diagnosis and treatment, failure to diagnose or treat, and the systems and equipment used to deliver
care. Adverse effects may be preventable or non-preventable.
Antibody (pl: antibodies): Antibodies (also known as immunoglobulins, abbreviated to Ig) are large proteins that
are found in blood or other body fluids. Antibodies are used by the immune system to identify and neutralise foreign
objects, such as bacteria and viruses.
Automatic substitution: The practice whereby a pharmacist is obliged to dispense one medicine instead of another
equivalent and interchangeable medicine due to national or local requirements without consulting with the prescriber.
Bioequivalence: Two medicinal products containing the same active substance are considered bioequivalent if
they are pharmaceutically equivalent or pharmaceutical alternatives and their bioavailabilities (rate and extent) after
administration in the same molar dose lie within acceptable predefined limits. These limits are set to ensure comparable
in vivo performance, i.e. similarity in terms of safety and efficacy.
Biopharmaceuticals/Biotechnology-derived medicines: A medicinal product or a vaccine that consists of or has
been produced by the use of living organisms. Often recombinant DNA (a form of DNA that does not exist naturally
and which combines DNA sequences that would not normally occur together in order to establish new functions) forms
the basis for biotechnologically manufactured products. Examples include therapeutic proteins such as antibodies,
insulins or interleukins; but also vaccines, nucleic acid or tissues and cells.
Biological medicine (also called biopharmaceutical medicine, biotechnology medicine or biotherapeutic
medicinal product): The active substance of a biological medicinal product is a biological substance. A biological
substance is a substance that is produced by or extracted from a biological source. A combination of physico-chemicalbiological testing, the production process and control is needed to characterise it and determine its quality.
Biosimilar medicine: A biosimilar medicine is a highly similar version of an already-approved biological medicine, in
terms of quality, safety and efficacy.
31
WHO definition (also called a similar biotherapeutic product): A biotherapeutic product which is similar in terms of
quality, safety and efficacy to an already-licensed reference biotherapeutic product.
EMA definition: A biological medicine that is developed to be similar to an existing biological medicine. When
approved, its variability and any differences between it and its reference medicine will have been shown not to affect
safety or effectiveness.
FDA definition: A biological product that is highly similar to a US-licensed reference biological product, notwithstanding
minor differences between the biological product and the reference product in terms of safety, purity and potency of
the product.
Biotechnology: The United Nations Convention on Biological Diversity defines biotechnology as “any technological
application that uses biological systems, living organisms or derivatives thereof, to make or modify products or
processes for specific use”.
Chemical medicine/drug (also called small molecule medicine): A medicine which is manufactured without the
involvement of living organisms. These contain chemical compounds with defined structures and characteristics.
Insulin: A hormone produced in the body that regulates the amount of glucose in the blood.
Interchangeability: The practice of changing one medicine for another that is expected to achieve the same clinical
effect in a given clinical setting and in any patients, or with the agreement of the prescriber.
International non-proprietary name (INN): This name facilitates the identification of pharmaceutical substances or
active pharmaceutical ingredients. Each INN is a unique name that is globally recognized and is public property, and is
assigned by the World Health Organization.
Master cell bank (MCB): Homogeneous cell suspension derived from the original cell line. It is stored frozen in the
vapour phase above liquid nitrogen in equal portions of uniform composition, one or more of which are used for the
production of the manufacturer’s working cell bank.
Molecule: The smallest particle of a substance that has all of the physical and chemical properties of that substance.
Molecules are made up of one or more atoms held together by strong chemical bonds. If they contain more than one
atom, the atoms can be the same (e.g. an oxygen molecule has two oxygen atoms) or different (e.g. a water molecule
has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins, can be made up of many
thousands of atoms.
Comparability exercise: Head-to-head comparison of a biotherapeutic product with a licensed originator product
with the goal to establish safety, efficacy and quality. Products should be compared in the same study using the same
procedures.
Monoclonal antibody: A class of antibody produced in the laboratory by a single clone of cells (parent cell or cell line)
consisting of identical antibody molecules.
DNA (Deoxyribonucleic Acid): DNA is a nucleic acid that contains the genetic information used in the development
and functioning of all cellular organisms. DNA contains the genetic code that controls the production of proteins in all
living things.
Originator product (also called innovator product): A medicine which has been licensed by national regulatory
authorities on the basis of a full registration dossier, i.e. that the approved indication(s) for use were granted on the
basis of full quality, safety and efficacy data.
Efficacy: The ability of a drug or medicine to produce the desired therapeutic effect when administered to a human.
European Medicines Agency (EMA): The EMA is responsible for approving all medicines before they are made
available to doctors and patients in the 28 member states of the European Union.
Patent: A patent is a set of exclusive rights granted by a state (national government) to an inventor or their assignee
for a limited period of time in exchange for public disclosure of its invention. Typically, however, a patent application
must include one or more claims defining the invention which must be new, non-obvious, and useful or industrially
applicable.
Erythropoietin: a hormone released from the kidneys and the liver in response to low oxygen concentrations in the
blood. It controls the rate of red blood cell production.
Pharmacovigilance: The science and activities relating to the detection, assessment, understanding and prevention of
adverse effects or any other drug-related problems.
US Food and Drug Administration (FDA): The FDA is responsible for approving all medicines before they are made
available to doctors and patients in the United States.
Protein: Large organic compounds made of amino acids arranged in a chain. Proteins are essential parts of organisms
and participate in virtually every process within cells.
Generic medicine: A generic medicine contains the same active pharmaceutical ingredient as and is bioequivalent
to an original branded medicine. Since generic medicines are identical in the active pharmaceutical substance, dose,
strength, route of administration, safety, efficacy and intended use, they can substituted for the original branded
medicine.
Reference product: A reference biotherapeutic product is used as the comparator for head-to-head comparability
studies with the similar biotherapeutic product (biosimilar) in order to show similarity in terms of quality, safety and
efficacy. Only an originator product which was licensed on the basis of a full registration dossier (full quality, pre-clinical
and clinical data) can serve as a reference product.
Immune system: The collection of mechanisms (or collection of biological substances and processes) within the body
that protect against disease by identifying and killing pathogens (e.g. viruses and bacteria).
Risk management plan (RMP): The activities that will ensure that patients continue to be safe and experience benefit
from a medicinal ingredient. These plans include pharmacovigilance plans among many other elements.
Immune response: A defence mechanism by the body in response to an invading substance, e.g. to bacteria, viruses
and substances recognised as foreign and possibly harmful, through mechanisms such as antibody production, cellmediated response, or allergic or anaphylactic reaction.
Substitution: The practice of dispensing one medicine instead of another equivalent interchangeable at the pharmacy
level without informing the prescriber.
Immunogenicity: The ability of a substance to trigger an immune response or reaction, e.g. the development of
specific antibodies, cell-mediated response, or allergic or anaphylactic reaction.
Switching: Decision by the treating physician to exchange one medicine for another medicine with the same
therapeutic intent in patients who are undergoing treatment.
Impurity: Any component present in the drug substance or drug product that is not the desired product, a productrelated substance, or inert substance including buffer components.
32
33
References
1. Bud, R. The Uses of Life: A History of Biotechnology. Cambridge University Press 1–5 (1993)
2. Reichert, J.M. Trends in US approvals: new biopharmaceuticals and vaccines. Trends in biotechnology 24, 293–8 (2006)
3. Mellstedt, H., Niederwieser, D. & Ludwig, H. The challenge of biosimilars. Annals of Oncology: official journal of
the European Society for Medical Oncology / ESMO 19, 411–9 (2008)
4. Büttel, I.C. et al. Taking immunogenicity assessment of therapeutic proteins to the next level. Biologicals: journal of
the International Association of Biological Standardization 39, 100–9 (2011)
5. Crommelin, D.J.A. et al. Shifting paradigms: biopharmaceuticals versus low molecular weight drugs. International
Journal of Pharmaceutics 266, 3–16 (2003)
6. EuropaBio. Guide to Biosimilars: A Focus on Biosimilar Medicines (2011)
7. Covic, A. & Kuhlmann, M.K. Biosimilars: recent developments. International Urology and Nephrology 39, 261–6 (2007)
8. Simoens, S. A European perspective on the market accessibility of biosimilars. Biosimilars 2, 33–40 (2012)
9. Weise, M. et al. Biosimilars: what clinicians should know. Blood 120, 5111–7 (2012)
10. Schellekens, H. How similar do “biosimilars” need to be? Nature biotechnology 22, 1357–9 (2004)
11. Giezen, T.J., Mantel-Teeuwisse, A.K. & Leufkens, H.G.M. Pharmacovigilance of biopharmaceuticals: challenges
remain. Drug safety: an international journal of medical toxicology and drug experience 32, 811–7 (2009)
12. Schellekens, H. Factors influencing the immunogenicity of therapeutic proteins. Nephrology, dialysis,
transplantation: official publication of the European Dialysis and Transplant Association – European Renal
Association 20 Suppl 6, 3–9 (2005)
13. Schellekens, H. Biosimilar therapeutics – what do we need to consider? NDT plus 2, i27–i36 (2009)
14. World Health Organization. Guidelines on evaluation of similar biotherapeutic products (SBPs). Expert Committee on
Biological Standardization. Geneva (2009)
15. European Medicines Agency. Questions and answers on biosimilar medicines (similar biological medicinal products)
(2012). Accessed at: www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2009/12/WC500020062.pdf
16. Schneider, C.K. Biosimilars in rheumatology: the wind of change. Annals of the Rheumatic Diseases 72, 315–8 (2013)
17. European Medicines Agency. Scientific guidance documents on biosimilar medicines. Accessed at:
www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp
18. European Commission. What you need to know about biosimilar medicinal products; a consensus information
document (2013). Accessed at: http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_report_en.pdf
19. European Generic Medicines Association. Biosimilars Handbook (2011)
20. Schneider, C.K. et al. Setting the stage for biosimilar monoclonal antibodies. Nature biotechnology 30, 1179–85 (2012)
21. Minghetti, P., Rocco, P., Cilurzo, F., Vecchio, L. Del & Locatelli, F. The regulatory framework of biosimilars in the
European Union. Drug Discovery Today 17, 63–70 (2012)
22. Kay, J. Biosimilars: a regulatory perspective from America. Arthritis Research & Therapy 13 (2011)
23. Health Canada. Release of guidance for sponsors: Information and submission requirements for subsequent entry
biologics (2010). Accessed at:
www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-demande/guides/seb-pbu/notice-avis_seb-pbu_2010-eng.php
24. Generics and Biosimilars Initative. Canadian guidelines for biosimilars (2010). Accessed at:
www.gabionline.net/Guidelines/Canadian-guidelines-for-biosimilars
25. European Medicines Agency. European public assessment reports (2013). Accessed at:
www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d125
26. Weise, M. et al. Biosimilars – why terminology matters. Nature Biotechnology 29, 690–3 (2011)
27. Knezevic, I. & Griffiths, E. Biosimilars – global issues, national solutions. Biologicals: Journal of the International
Association of Biological Standardization 39, 252–5 (2011)
28. Thorpe, R. Terminology for biosimilars – a confusing minefield. Generics and Biosimilars Initiative Journal 1, 13–16 (2012)
29. Mellstedt, H. The future of biosimilars. Hospital Pharmacy Europe (2010). Accessed at:
www.hospitalpharmacyeurope.com/default.asp?title=The_future_of_biosimilars_&page=article.display&article.id=20840
30. Generics and Biosimilars Initative. Development of biosimilars (2011). Accessed at:
www.gabionline.net/Biosimilars/Research/Development-of-biosimilars
31. Sandoz. Biosimilar Development. Accessed at:
www.sandoz-biosimilars.com/biosimilars2/development_of_biosimilars.shtml (2013)
32. IMS Health. Shaping the biosimilars opportunity: A global perspective on the evolving biosimilars landscape (2011)
33. C. Dunn. Biosimilar accessible market: Size and biosimilar penetration. IMS Health (2012)
34
34. BioTrends Research Group. Biosimilars Advisory Service; Corporate Strategies (2013)
35. European Medicines Agency. Guideline on similar biological medicinal products containing monoclonal antibodies
– non-clinical and clinical issues (2012). Accessed at:
www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500128686.pdf
36. European Medicines Agency. European Medicines Agency recommends approval of first two monoclonal
antibody biosimilars (2013). Accessed at: www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/
2013/06/news_detail_001837.jsp&mid=WC0b01ac058004d5c1
37. Rotenstein, L.S., Ran, N., Shivers, J.P., Yarchoan, M. & Close, K.L. Opportunities and Challenges for Biosimilars:
What’s on the Horizon in the Global Insulin Market? Clinical Diabetes 30, 138–150 (2012)
38. Generics and Biosimilars Initative. Biosimilar G-CSF prescribed more than originator (2013). Accessed at:
www.gabionline.net/Biosimilars/News/Biosimilar-G-CSF-prescribed-more-than-originator
39. Kessler, M., Goldsmith, D. & Schellekens, H. Immunogenicity of biopharmaceuticals. Nephrology, dialysis,
transplantation: official publication of the European Dialysis and Transplant Association – European Renal
Association 21 Suppl 5, 9–12 (2006)
40. EuropaBio. EuropaBio & Biosimilar Medicines (2008)
41. International Alliance of Patients’ Organizations. Briefing Paper on Biosimilar Medicines (2006)
42. Koren, E., Zuckerman, L. & Mire-Sluis, A. Immune Responses to Therapeutic Proteins in Humans – Clinical
Significance, Assessment and Prediction. Current Pharmaceutical Biotechnology 3, 349–360 (2002)
43. Abraham, I. & MacDonald, K. Clinical safety of biosimilar recombinant human erythropoietins. Expert Opinion on
Drug Safety 11, 819–40 (2012)
44. World Health Organization. Pharmacovigilance (2013). Accessed at:
www.who.int/medicines/areas/quality_safety/safety_efficacy/pharmvigi/en/index.html
45. Medicines and Healthcare Products Regulatory Agency. Medicines safety monitoring (2013). Accessed at:
www.mhra.gov.uk/Safetyinformation/Howwemonitorthesafetyofproducts/Medicines/Pharmacovigilance/index.htm
46. Zuñiga, L. & Calvo, B. Biosimilars: pharmacovigilance and risk management. Pharmacoepidemiology and Drug
Safety 19, 661–9 (2010)
47. World Health Organization. International Nonproprietary Names (2013). Accessed at:
www.who.int/medicines/services/inn/en/
48. Medicines and Healthcare Products Regulatory Agency. Biosimilar products (2008). Accessed at:
www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON084739
49. European Commission. Pharmacovigilance Directive (2012). Accessed at:
www.ec.europa.eu/health/files/eudralex/vol-1/dir_2010_84/dir_2010_84_en.pdf
50. Vermeer, N.S. et al. Traceability of biopharmaceuticals in spontaneous reporting systems: a cross-sectional study in
the FDA Adverse Event Reporting System (FAERS) and EudraVigilance databases. Drug safety: an international
journal of medical toxology and drug experience. 36, 617–25 (2013)
51. Ebbers, H.C., Crow, S.A, Vulto, A.G. & Schellekens, H. Interchangeability, immunogenicity and biosimilars. Nature
Biotechnology 30, 1186–90 (2012)
52. Rovira, J., Espín, J., García, L. & Labry, A.O.De. The impact of biosimilars’ entry in the EU market. Andalusian School
of Public Health (2011)
53. Garcia, R. Biological Drug Regulation. Presentation at the Alianza Latina 7th Forum (2012)
54. Castanheira, L.G., Barbano, D.B.A. & Rech, N. Current development in regulation of similar biotherapeutic products
in Brazil. Biologicals: Journal of the International Association of Biological Standardization 39, 308–11 (2011)
55. Generics and Biosimilars Initative. Prospects for producing follow-on biological products in Brazil (2013). Accessed at:
www.gabionline.net/Biosimilars/Research/Prospects-for-producing-follow-on-biological-products-in-Brazil
56. Generics and Biosimilars Initative. Dr Reddy’s plans EU launch for biosimilar rituximab (2012). Accessed at:
www.gabionline.net/Biosimilars/News/Dr-Reddy-s-plans-EU-launch-for-biosimilar-rituximab
57. Dr. Reddy’s. Dr. Reddy’s launches RedituxTM – Monoclonal Antibody Treatment for Non-Hodgkin’s Lymphoma (2007).
Accessed at: www.drreddys.com/products/popups/reditux.htm
58. Generics and Biosimilars Initative. “Similar biologics” approved and marketed in India (2012). Accessed at:
www.gabionline.net/Biosimilars/General/Similar-biologics-approved-and-marketed-in-India
59. Thorpe, R. Unwanted Immunogenicity of Biosimilars and Non-Innovator Biologicals. Presentation (2012)
60. Rathore, A. Guidelines on similar biologics: regulatory requirements for marketing authorization in India. PDA
Journal of Pharmaceutical Science and Technology / PDA 66, 393 (2012)
61. European Generic Medicines Association. Frequently asked questions about biosimilar medicines (2011). Accessed at:
www.egagenerics.com/images/factsheet/EGA_factsheet_07.pdf
35
62. Feijo-Azevedo, V., Ricardo-Felippe, L. & Magalhaes-Machado, D. Opinion of some Brazilian rheumatologists about
biosimilars. Brazilian Journal of Rheumatology 51, 662–671 (2011)
63. Salem, L. & Harvie, B. Biosimilar medicines and their use: the nurse’s role and responsibility. Renal Society of
Australasia Journal 6, 76–80 (2010)
Endnotes
i The information provided in this section is based on the guidelines for the approval of biosimilar medicines of the
World Health Organization and European Medicines Agency unless stated otherwise.13,14,17
ii Please visit www.patientsorganizations.org/biosimilars for more details about the workshop and a list of attendees.
Appendix
Biosimilar medicines that have been approved in the European Union since 2006 (as of October 2013, taken
from the website of the European Medicines Agency)25
International
Non-Proprietary
Name (INN) of
active substance
Brand name
Originator
product
Therapeutic area
Date of
authorization
Marketing
authorization holder
Omnitrope
Genotropin
Dwarfism, Pituitary
Prader-Willi Syndrome,
Turner Syndrome
12/04/2006
Sandoz GmbH
Valtropin*
Humatrope
Dwarfism, Pituitary
Turner Syndrome
24/04/2006
BioPartners GmbH
Somatropin
Chronic anaemia,
kidney failure
Binocrit
Epoetin Alfa
Epoetin alfa
Hexal
Erypro/Eprex
Sandoz GmbH
28/08/2007
Chronic anaemia,
kidney failure, cancer
Medice Arzneimittel Pütter
GmbH & Co. KG
Abseamed
Epoetin Zeta
Silapo
Retacrit
Erypro/Eprex
Anaemia, blood
transfusion, cancer,
kidney failure
18/12/2007
Tevagrastim
Teva Generics GmbH
15/09/2008
Filgrastim
Ratiopharm*
Neupogen
Cancer, hematopoietic
stem cell transplantation,
neutropenia
Nivestim
08/06/2010
Inflectra
Remsima
CT Arzneimittel GmbH
Ratiopharm GmBH
06/02/2009
Filgrastim Hexal
Sandoz GmbH
Hexal GmbH
Hospira UK Ltd
Hospira UK Ltd
Remicade
*Valtropin and Filgrastim Ratiopharm have been withdrawn
36
Hospira UK Ltd
Ratiopharm GmBH
Zarzio
Infliximab
Stada Arzneimittel GmbH
Ratiograstim
Biograstim
Filgrastim
Hexal GmbH
Rheumatoid arthritis,
moderate Crohn’s Disease
10/09/2013
Celltrion Healthcare
Hungary Kft
49–51 East Road, London N1 6AH, United Kingdom
Tel: +44 20 7250 8280 Fax: +44 20 7250 8285 Email: [email protected]
www.patientsorganizations.org